Cholesterol is an essential component of animal cell membranes. As a structural component it is involved in maintaining the integrity of cells. By regulating the precise fluidity of cellular membranes cholesterol plays a role in the control of many cellular functions.
Cells are capable of deriving necessary cholesterol from either de novo synthesis or an external source. For hepatic cells the external source may be dietary cholesterol transported via chylomicron remnants. For extrahepatic cells the external source is low density lipoproteins (LDL). LDL are formed in the circulating blood from interactions and exchanges between liver produced very low density lipoproteins and high density lipoproteins. The cholesterol associated with LDL could have originally come from either hepatic synthesis or dietary cholesterol. Normally, a healthy cell supplied with pre-formed cholesterol, regardless of the original source, initiates a feedback mechanism which inhibits de novo synthesis of cholesterol in that cell.
Increased cholesterol content of the tumor cell's membranes results in physical changes and modifications of the functional activities of the membranes. These alterations are advantageous for cell proliferation.
Cancer cells assume a strategy which provides them with a selective growth advantage. One biochemical alteration which occurs shortly after the initiation of the cancer state is that the initiated cells devise a means for protecting de novo cholesterol synthesis from any normal regulatory mechanisms. Cancer cells accomplish this by modifying the active site of HMGCoA reductase, the primary cholesterol rate-limiting enzyme.
Overall in vivo and in vitro studies show that cancer cells lack feedback control of de novo cholesterol synthesis.
Regardless of the reasons, de novo cholesterol synthesis appears to be a prerequisite for tumor cell growth. HMGCoA reductase activity is about ten times greater in cancer cells as compared to normal cells. Abnormalities in biosynthetic regulation of lipids, especially cholesterol, are early events in tumorgenesis and are the basis for many phenotypic variations such as membrane fluidity, ion permeability, substrate transport and the activities and affinities of membrane bound enzymes and receptors.
Metastasis occurs when a tumor invades surrounding tissue and/or spreads throughout the body to begin new tumors at distant sites. Elevated cholesterol levels are associated with a number of invasive tumors. Survival rate is high for those with localized malignancy and very low for individuals when metastasis has occurred. Tumor cells are often surrounded by microvesicles. Van Blitterswijk et al. Bio Chem. Bio Phys. Acta. 467:309 (1974) propose that budding and shedding of these cell surface microvesicle projections occurs at plasma membrane loci that are more rigid then normal and cholesterol enriched. Besides having a role in meeting the nutritional needs of the proliferating cell, or serving as a source of excess membrane for cell division it has been proposed that these vesicles form a target for post immune response thus overloading the immune system and diverting the response from destroying the tumor cell. The shedding of these tumor vesicles may very well have a primary role in metastasis.
Japanese epidemeological studies (R.K. Cameron, et al., Grann., 69:679 (1981) have reported that people who drink milk had the lowest incidence of stomach cancer, the major form of cancer in Japan. Other studies have shown a similar response for colon cancer in the American population. Inhibition of tumor cell proliferation in animal models has been reported by the use of fermented dairy products. This response has been attributed to a product of the fermentating microorganisms. (G.W. Reddy, et al., J. Nat'l. Cancer Inst., 50:815 (1973); E.P.C. Esser, et al., Milchwissenschaft, 838:257 (1983); A.D. Ayebo, et. al., J. Dairy Sci., 64:2318 (1981); L.A. Schackelford, et al., Nutrition and Cancer, 5:159 (1983); K.M. Shahani, et al., J. Food Prot., 46:385 (1983)).
Skim milk contains two cholesterogenic inhibitors. One of these is orotic acid (OA) which inhibits acetoacyl CoA thiolase, the second enzyme in the cholesterol biosynthetic pathway and a second inhibitor IMIC (Inhibitor of Mevalonate Incorporation into Cholesterol) which prevents squalene synthetase from catalyzing the formation of squalene along the cholesterol biosynthetic pathway, (A.A. Ahmed, et al., Atherosclerosis, 32:347 (1979); B.J. Dull, et al., Atherosclerosis, 49:231 (1983); C.M. Papa, Milchwissenschaft, 37:257 (1982) all of which are herein incorporated by reference). Surprisingly, it has been found that since IMIC exerts its action for supressing cholesterol genesis at a site other than the normal rate-limiting enzyme, its use in tumor systems was shown to circumvent the adaptive inhibition of feedback in neoplastic cells. By preventing the mandatory requirement of cholesterol synthesis in the neoplastic cell, the growth of the tumor is supressed. Since endogenous synthesis of cholesterol is universally required in neoplastic cells for their survival, IMIC can be employed as an antineoplastic agent against virtually any neoplastic disease and is therefore applicable in the treatment of all cancers including for example, leukemias, bronchogenic carcinoma of the lung, adenocarcinomas of the colon and rectum, astrocytomas, melanomas and mammary carcinomas.